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Details

Stereochemistry ACHIRAL
Molecular Formula C32H29N5O2
Molecular Weight 515.6062
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ENZASTAURIN

SMILES

Cn1cc(c2ccccc21)C3=C(c4cn(C5CCN(CC5)Cc6ccccn6)c7ccccc47)C(=O)N=C3O

InChI

InChIKey=AXRCEOKUDYDWLF-UHFFFAOYSA-N
InChI=1S/C32H29N5O2/c1-35-19-25(23-9-2-4-11-27(23)35)29-30(32(39)34-31(29)38)26-20-37(28-12-5-3-10-24(26)28)22-13-16-36(17-14-22)18-21-8-6-7-15-33-21/h2-12,15,19-20,22H,13-14,16-18H2,1H3,(H,34,38,39)

HIDE SMILES / InChI

Molecular Formula C32H29N5O2
Molecular Weight 515.6062
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Enzastaurin is a serine/threonine kinase inhibitor that showed antiangiogenic, antiproliferative, and proapoptotic properties in vitro and antitumor activity in vivo in a xenograft Waldenström macroglobulinemia (WM) model. Enzastaurin (LY317615) is a potent PKCβ selective inhibitor. Enzastaurin suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis. Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. Eli Lilly discontinued development of enzastaurin after top-line data from the double-blind, international Phase III PRELUDE trial in 758 DLBCL patients showed that enzastaurin missed the primary endpoint of improving DFS vs. placebo.

Originator

Curator's Comment:: # Eli Lilly

Approval Year

Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Reduction of HLA-DR+ lymphocytes after treatment with enzastaurin in patients with metastatic thyroid cancer.
2008
Enzastaurin, an inhibitor of PKCbeta, Enhances Antiangiogenic Effects and Cytotoxicity of Radiation against Endothelial Cells.
2008 Dec
Exploring multi-targeting strategies for the treatment of gliomas.
2008 Dec
Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells.
2008 Dec 2
Targeted treatment and new agents in diffuse large B-cell lymphoma.
2008 Jul
[Protein kinases C: a new cytoplasmic target].
2008 Jul-Aug
[Recent therapeutic progress in non-Hodgkin lymphoma: focusing on diffuse large B-cell lymphoma and follicular lymphoma].
2008 Oct
Protein kinase C beta in malignant pleural mesothelioma.
2008 Oct
Novel therapies in breast cancer: what is new from ASCO 2008.
2008 Oct 1
Advances in the treatment of monoclonal gammopaties: The emerging role of targeted therapy in plasma cell dyscrasias.
2008 Sep
Molecular pathways involved in the synergistic interaction of the PKC beta inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells.
2008 Sep 2
MET/PKCbeta expression correlate with metastasis and inhibition is synergistic in lung cancer.
2009
Current available therapies and future directions in the treatment of malignant gliomas.
2009
In Vivo Measurements of Tumor Metabolism and Growth after Administration of Enzastaurin Using Small Animal FDG Positron Emission Tomography.
2009
Design of Phase II cancer trials for evaluation of cytostatic/cytotoxic agents.
2009
Role of PKCbeta in hepatocellular carcinoma cells migration and invasion in vitro: a potential therapeutic target.
2009
Perspectives of protein kinase C (PKC) inhibitors as anti-cancer agents.
2009 Apr
Synergistic anti-tumor efficacy of lovastatin and protein kinase C-beta inhibitor in hepatocellular carcinoma.
2009 Aug
Combination of enzastaurin and pemetrexed inhibits cell growth and induces apoptosis of chemoresistant ovarian cancer cells regulating extracellular signal-regulated kinase 1/2 phosphorylation.
2009 Aug 18
Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents.
2009 Dec
Carboplatin and paclitaxel in combination with oral enzastaurin in advanced ovarian or primary peritoneal cancer: results from a safety lead-in study.
2009 Dec
A phase II study of oral enzastaurin in patients with metastatic breast cancer previously treated with an anthracycline and a taxane containing regimen.
2009 Dec
Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling.
2009 Feb 12
Protein kinase Cbeta is an effective target for chemoprevention of colon cancer.
2009 Feb 15
In vivo/ex vivo and in situ assays used in cancer research: a brief review.
2009 Jan
Antiangiogenic drugs in ovarian cancer.
2009 Jan 13
Enzastaurin shows preclinical antitumor activity against human transitional cell carcinoma and enhances the activity of gemcitabine.
2009 Jul
Quantitative in situ detection of phosphoproteins in fixed tissues using quantum dot technology.
2009 Jul
Protein kinase C-beta II (PKC-beta II) expression in patients with colorectal cancer.
2009 Jun
Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1alpha-dependent pathway in multiple myeloma.
2009 Jun 15
Molecular targeting of the PKC-beta inhibitor enzastaurin (LY317615) in multiple myeloma involves a coordinated downregulation of MYC and IRF4 expression.
2009 Mar
PKCbeta is essential for the development of chronic lymphocytic leukemia in the TCL1 transgenic mouse model: validation of PKCbeta as a therapeutic target in chronic lymphocytic leukemia.
2009 Mar 19
Overview of current and future biologically based targeted therapies in head and neck squamous cell carcinoma.
2009 Mar 2
[Role of PKCbeta in the malignant tumors and enzastaurin, a PKCbeta inhibitor].
2009 May
A phase I trial of enzastaurin in patients with recurrent gliomas.
2009 May 15
Synergistic effect of Sorafenib and Sunitinib with Enzastaurin, a selective protein kinase C inhibitor in renal cell carcinoma cell lines.
2009 May 18
Conformationally constrained analogues of diacylglycerol (DAG). 31. Modulation of the biological properties of diacylgycerol lactones (DAG-lactones) containing rigid-rod acyl groups separated from the core lactone by spacer units of different lengths.
2009 May 28
Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer.
2009 Sep
Enzastaurin (LY317615), a protein kinase C beta selective inhibitor, enhances antiangiogenic effect of radiation.
2010 Aug 1
Combined RNA-expression and 2D-PAGE-screening identifies comprehensive interaction networks affected after bortezomib or enzastaurin exposure of mantle cell lymphoma.
2010 Feb 15
Protein kinase Calpha: disease regulator and therapeutic target.
2010 Jan
Enzastaurin induces H2AX phosphorylation to regulate apoptosis via MAPK signalling in malignant glioma cells.
2010 Jan
Synergistic antifibrotic efficacy of statin and protein kinase C inhibitor in hepatic fibrosis.
2010 Jan
Recruitment of PKC-betaII to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70.
2010 Jan
Pharmacological aspects of the enzastaurin-pemetrexed combination in non-small cell lung cancer (NSCLC).
2010 Jan
MicroRNA-21 inhibitor sensitizes human glioblastoma cells U251 (PTEN-mutant) and LN229 (PTEN-wild type) to taxol.
2010 Jan 31
Protein kinase Cbeta modulates ligand-induced cell surface death receptor accumulation: a mechanistic basis for enzastaurin-death ligand synergy.
2010 Jan 8
Phase II, double-blinded, randomized study of enzastaurin plus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer.
2010 Mar
Long-term follow-up of chemonaive patients with asymptomatic metastatic colorectal cancer treated with enzastaurin in a window of opportunity phase II study.
2010 May
A window of opportunity phase II study of enzastaurin in chemonaive patients with asymptomatic metastatic colorectal cancer.
2010 May
Patents

Sample Use Guides

1125 mg loading dose then 500 mg, oral, daily, until disease progression or maximum of 3 years
Route of Administration: Oral
In the BON1 cell line Enzastaurin inhibited cell proliferation at 5 and 10 uM by inducing caspase-mediated apoptosis, and reduced phosphorylation of glycogen synthetase kinase 3β (GSK3β) and of Akt, both downstream targets of PKC pathway and pharmacodynamic markers for Enzastaurin.
Substance Class Chemical
Created
by admin
on Sat Jun 26 16:00:29 UTC 2021
Edited
by admin
on Sat Jun 26 16:00:29 UTC 2021
Record UNII
UC96G28EQF
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
ENZASTAURIN
INN   MI   WHO-DD  
INN   USAN  
Official Name English
ENZASTAURIN [MI]
Common Name English
LY317615
Code English
ENZASTAURIN [WHO-DD]
Common Name English
LY-317615
Code English
3-(1-METHYL-1H-INDOL-3-YL)-4-(1-(1-(PYRIDIN-2-YLMETHYL)PIPERIDIN-4-YL)-1H-INDOL-3-YL)-1H-PYRROLE-2,5-DIONE
Systematic Name English
ENZASTAURIN [INN]
Common Name English
1H-PYRROLE-2,5-DIONE, 3-(1-METHYL-1H-INDOL-3-YL)-4-(1-(1-(2-PYRIDINYLMETHYL)-4-PIPERIDINYL)-1H-INDOL-3-YL)-
Systematic Name English
DB-102
Code English
ENZASTAURIN [USAN]
Common Name English
DB102
Code English
Classification Tree Code System Code
FDA ORPHAN DRUG 277209
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
NCI_THESAURUS C2089
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
FDA ORPHAN DRUG 208505
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
Code System Code Type Description
INN
8426
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
PRIMARY
PUBCHEM
176167
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
PRIMARY
EPA CompTox
170364-57-5
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
PRIMARY
ChEMBL
CHEMBL300138
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
PRIMARY
CAS
170364-57-5
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
PRIMARY
WIKIPEDIA
ENZASTAURIN
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
PRIMARY
EVMPD
SUB33466
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
PRIMARY
FDA UNII
UC96G28EQF
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
PRIMARY
MESH
C504878
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
PRIMARY
DRUG BANK
DB06486
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
PRIMARY
NCI_THESAURUS
C77392
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
PRIMARY
MERCK INDEX
M4926
Created by admin on Sat Jun 26 16:00:29 UTC 2021 , Edited by admin on Sat Jun 26 16:00:29 UTC 2021
PRIMARY Merck Index
Related Record Type Details
SALT/SOLVATE -> PARENT
SALT/SOLVATE -> PARENT
SALT/SOLVATE -> PARENT
TARGET -> INHIBITOR
Related Record Type Details
ACTIVE MOIETY